Several mechanisms can cause increased Ras signaling, which is a common finding in many human cancers. Activating mutations in Ras are commonly found in skin cancers. Genetic studies in the mouse showed that gain of function perturbations in the Ras signaling pathway increased skin tumor susceptibility or were sufficient to cause tumors. Other studies indicated that p53, p16(INK4a), and p19(ARF) tumor suppressor function played critical roles in determining if keratinocytes underwent malignant transformation in response to increased Ras signaling. Classically, extracellular growth factors bind to and induce dimerization of transmembrane receptor tyrosine kinases (RTKs), which initiates the RAS/MAPK intracellular signaling cascade. Upregulation of the Epidermal Growth Factor Receptor (EGFR) family and/or their ligands is a common finding in skin cancer. Consequently, their role in the pathogenesis of skin cancer has been the focus of many studies. Much less is known about the possible role of Fibroblast Growth Factor Receptor (FGFR) initiated Ras signaling in skin tumor development. Keratin 14 (K14) promoter driven misexpression of keratinocyte growth factor (kgf aka Fgf7) in the epidermis, at relatively high levels, caused skin abnormalities that were perinatal lethal in 13/18 founders. The 5 surviving pups had lower transgene expression, but also displayed a range of skin phenotypes. Interestingly, discreet areas of skin showed signs of transformation at 4 months of age, but it is not known if these changes progressed to tumors. Because the K14 promoter begins to be expressed in the developing epidermis at about embryonic day 14.5, it is difficult to determine to what extent the observed phenotypes were due to developmental defects. Thus, the consequences of increased, particularly greatly increased, FGFR signaling in postnatal skin remains unclear. Here, we propose to use an inducible K14 Cre transgene to recombine a highly expressed, conditional Fgf4 transgene and thereby misexpress high levels of Fgf4 in the skin of postnatal mice. The specific aims of the project are (1) to characterize the histological and molecular changes that occur in the skin over time in response to postnatal increased FGFR signaling; (2) to determine if prolonged, increased FGFR signaling leads to skin cancer. The proposed studies will provide insights into the potential role of FGFR signaling in the pathogenesis of skin cancer. In addition, because of the great interest in KGF-based therapies to promote wound healing, a greater understanding of the consequences of increased FGFR signaling in the skin is important to prevent potentially detrimental side effects.